Tuberculosis (TB) is the leading cause of death among HIV-infected adults in Africa and other parts of the world. Recently, the potential for widespread transmission of multidrug and extensively drug resistant (MDR and XDR) TB among HIV-infected persons in hospitals and other congregate settings has been reported, and may undermine advances in survival achieved by increasing global access to antiretroviral therapy. However, epidemiological and laboratory observations on the infectiousness of MDR-TB patients and the transmissibility and virulence of MDR-M. tuberculosis strains have been conflicting. Some data suggest TB/HIV patients are more infectious than HIV-uninfected/TB patients, while others suggest the opposite. Other work suggests that MDR-TB strains are heterogeneous in transmissibility and virulence as a consequence of genetic mutations responsible for drug resistance. Greater understanding of the airborne transmission of MDR-TB strains among HIV co-infected persons in clinical settings is essential to achieving better transmission control. In this career development proposal, the applicant plans to test the hypothesis that HIV co-infected MDR-TB patients are potentially less infectious than HIV-uninfected MDR-TB patients by comparing their production of culturable cough aerosols and by comparing the infection rate of exposed sentinel guinea pigs after controlling for cough aerosol production. He will also test the hypothesis that MDRTB strains of attenuated virulence are preferenitially associated with HIV co-infected MDR-TB patients compared to HIV-uninfected patients by examining the histopathology of infected guinea pigs exposed to both groups. He will conduct the proposed work with HIV-infected and HIV-uninfected MDR-TB patients in South Africa and will further develop proficiency with the use of an aerosol exposed guinea pig model of TB. He also proposes to learn microbiologic, genetic fingerprinting, and cough aerosol sampling techniques to achieve his research goals. With the support of his mentors and collaborators, he will pursue a rigorous research training program to become an independent clinical and translational investigator on MDR-M. tuberculosis virulence and the effeqt of HIV on the spread of MDR-TB.

Public Health Relevance

MDR-M. tuberculosis transmission threatens global TB control, especially in populations where.HIV co-infection is prevelant. Improved understanding of how pathogen and host factors influence MDR-M. tuberculosis transmission is essential to reducing the spread of MDR-TB to individuals with HIV co-infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
Application #
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Jacobs, Gail G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Yuen, Courtney M; Amanullah, Farhana; Dharmadhikari, Ashwin et al. (2015) Turning off the tap: stopping tuberculosis transmission through active case-finding and prompt effective treatment. Lancet 386:2334-43
Dharmadhikari, Ashwin S; Kabadi, Mohan; Gerety, Bob et al. (2013) Phase I, single-dose, dose-escalating study of inhaled dry powder capreomycin: a new approach to therapy of drug-resistant tuberculosis. Antimicrob Agents Chemother 57:2613-9
Dharmadhikari, Ashwin S (2013) Six degrees of separation: use of social network analysis to better understand outbreaks of nosocomial transmission of extensively drug-resistant tuberculosis. J Infect Dis 207:1-3
Dharmadhikari, Ashwin S; Mphahlele, Matsie; Stoltz, Anton et al. (2012) Surgical face masks worn by patients with multidrug-resistant tuberculosis: impact on infectivity of air on a hospital ward. Am J Respir Crit Care Med 185:1104-9
Dharmadhikari, Ashwin S; Basaraba, Randall J; Van Der Walt, Martie L et al. (2011) Natural infection of guinea pigs exposed to patients with highly drug-resistant tuberculosis. Tuberculosis (Edinb) 91:329-38
Dharmadhikari, Ashwin S; Nardell, Edward (2011) Serial acid fast bacilli smear and culture conversion rates over 26 weeks in a cohort of 93 sputum culture–positive tuberculosis (TB). Clin Infect Dis 52:554-6
Nardell, E; Dharmadhikari, A (2010) Turning off the spigot: reducing drug-resistant tuberculosis transmission in resource-limited settings. Int J Tuberc Lung Dis 14:1233-43